摘要
抑制蛋白-蛋白相互作用(PPI)的小分子药物向来是新药研发的难题,雅培公司创制的venetoclax是第一个真正意义上的PPI抑制剂。该药研发20年,历尽曲折与风险。本文从药物化学的视角简要介绍其研发过程。Venetoclax的研制涉及多种技术方法,包括用核磁共振(SAR by NMR),基于片段的药物发现(FBDD),X-射线晶体学指导基于蛋白结构的分子设计以及集中库的设计等。研发中两次更改靶标,由单一的靶标Bcl-x L蛋白改换成双靶标Bcl-x L/Bcl-2,最后聚焦为Bcl-2蛋白,彰显出研发的巨大风险性,见证了确证靶标的可药性(druggability)贯穿于从先导物到临床试验的全过程。作为口服治疗慢性淋巴白血病的药物,Venetoclax的创新性还表现出化学结构突破了"类药5规则"的限制,分子量为882的化合物足以屏蔽掉两个蛋白的结合热域(hot spots)也体现了构建化学结构的成功。
Discovery of small molecule drugs to interfere protein-protein interaction（PPI） has always been a difficult issue. As the first marketed drug by the inhibition of PPI in the true sense, discovery of venetoclax lasts twenty years through all obstacles and risk. This article concisely introduces the process of R ＆ D on venetoclax from the viewpoint of medicinal chemistry, which is characterized by integration of several technologies, including fragment-based drug discovery （ FBDD）, NMR （ SAR by NMR） and X-ray crystallography for structure-based drug design（ SBDD）, focus library synthesis, among others. It should be highlighted that switches of targets from Bcl-xL through Bcl-xL/Bcl-2 toward the sole Bcl-2 reveal a huge risk in the course of R ＆ D,indicating that validation of target （s） exists throughout from lead to clinic. Another point in venetoclax molecule is the violation of ＂Rule of Five＂. Small molecule drugs interfering with PPI frequently necessitate large size and lipophilic property to bind hot spots in PPI.
出处
《中国药物化学杂志》
CAS
CSCD
2017年第3期169-176,共8页
Chinese Journal of Medicinal Chemistry
